KR20170127056A - Extracranial implantable devices, systems and methods for the treatment of neurological disorders - Google Patents

Abstract

The present invention relates to methods, devices and systems used to treat neurological disorders through stimulation of epidermal elements of the trigeminal nerve ("TNS"). Particularly, the epidermal junctions of the trigeminal nerve located outside the skull of the face, namely, the orbital nerve, the pulmonary nerve, the pulmonary tunic, the temporal nerve, the temporal nervous system, the olfactory nerve, the ankle facial nerve, Minimal invasive methods of stimulation of nerves (collectively, also referred to as epidermal trigeminal nerve) are disclosed herein. Systems and devices and their application methods configured for therapeutic stimulation of trigonal neurons, such as epidermal trigeminal nerves, are also disclosed.

Description

[0001] The present invention relates to an extracranial implantable device, system and method for the treatment of neurological diseases,

Cross reference of related application

This application claims the benefit of U. S. Application No. 61 / 248,827, filed October 5, 2009, entitled " Devices and Methods for Treatment of Psychiatric Disorders, " U. S. Serial No. 61 / 289,829, filed December 23, 2009, entitled " Extracranial Implantable Devices, Systems and Methods for Treatment of Neuropsychiatric Disorders; U.S. Application Serial No. 61 / 305,514, filed February 17, 2010, entitled " Systems, Devices and Methods for Treatment of Neurological Disorders and Conditions "; No. 61 / 354,641, filed June 14, 2010, entitled " Extracranial Implantable Devices, Systems and Methods for Treatment of Neurological Disorders ", each application being hereby incorporated herein by reference in its entirety Are incorporated by reference.

This application is related to the following pending applications: Attorney Docket No. < RTI ID = 0.0 > US Application No. __________________________________________ [2010-396-2] filed as " Extracranial Implantable Devices, Systems and Methods for Treatment of Neuropsychiatric Disorders " Attorney Docket No. US Application No. __________________________________________ [2007-292-2] filed as 001659-5001-US, entitled " Systems, Devices and Methods for the Treatment of Neurological Disorders and Conditions "; Attorney Docket No. US Application No. __________________________________________ [2010-003-2], filed as " Devices, Systems and Methods for the Treatment of Neuropsychiatric Disorders ", assigned to the assignee of the present application, Are incorporated by reference.

The present invention generally relates to a nerve stimulation system, device and method of use thereof, and more particularly to a nerve stimulation system, device and method comprising at least one implantable electrode for stimulating epidermal, .

Neurological disorders such as epileptic seizures, acute or chronic brain disorders, coma, seizure disorders characterized by chronic headache or migraine, and disorders associated with movement have been treated with drugs. For example, seizure disorders frequently mentioned as epilepsy are initially treated with anticonvulsants. For some patients, anticonvulsants do not work properly, and individual epilepsy or nerve stimulation is given as a therapeutic option for these patients. Neurostimulation to treat epilepsy and seizure disorders involves stimulating the nervous system with Vagus Nerve Stimulation (VNS), which has been shown to be therapeutically useful and approved by the US Food and Drug Administration. In this method, the stimulation electrodes are surgically implanted into the vagus nerve from the neck. In addition to the complicated tasks associated with anesthesia, infection risk, cost, and other events when performing vagus nerve stimulation (VNS), many of the problems of vagus nerve stimulation (VNS) Lt; RTI ID = 0.0 > VNS < / RTI > device.

Therefore, other solutions are being sought. For example, intracranial implantable methods such as deep brain stimulation (DBS) on the display and reactive nerve stimulation (RNS) in the epileptic area can be used. Reactive nerve stimulation (RNS) employs a device that monitors the brain activity and delivers stimuli to end seizure disorders. However, these methods involve highly surgical procedures, since electrodes must be placed in the brain, on the surface of the brain, or near sensitive neurovascular structures. In addition, these treatments have increased side effects compared to other methods which are costly and less surgical. Despite these range of options, a significant proportion of patients have not recovered or experienced relief from neuropsychiatry even after multiple drug or surgical treatments.

An embodiment of the problem to be solved by the present invention is to provide a method for diagnosing and treating an orbital nerve, an ankle nerve, an ankle nerve, an ankle nerve, an ankle nerve, And to provide a system and apparatus configured to stimulate the skin or epidermal segments of the trigeminal nerve located in the face, including the jaw nerve. The present invention provides a method for treating neurological diseases using trigeminal nerve stimulation (TNS) using implantable and easy to use devices and systems as a minimal surgical procedure.

In another aspect of the invention, an implantable subcutaneous electrode assembly configured for trigeminal nerve stimulation is provided.

In another aspect of the invention, a method of treating a neurological disease using the implantable subcutaneous electrode assembly is provided.

The subcutaneous electrode assembly for trigeminal nerve stimulation is described below. In one embodiment, the subcutaneous electrode assembly comprises: a first electrode comprising a first pair of contacts configured for subcutaneous placement in a first region of a patient's face; A second electrode comprising a second pair of contacts configured for subdermal placement in a second region of the patient's face wherein the contacts of the first pair and the contacts of the second pair are electrically connected to the nerve And is configured to be implanted in both directions in close proximity to, adjacent to or in contact with at least one branch of the trigeminal nerve to treat the disease. At least one branch of the trigeminal nerve is selected from the group consisting of an eye nerve, an ophthalmic nerve, a chin nerve, a pulmonary hypertrophy, a cranial nerve, a temporal cranial nerve, an olfactory facial nerve, an olfactory nerve, a nerve and an anterior temporal nerve.

The subcutaneous electrode assembly for trigeminal nerve stimulation is described below. In one embodiment, the subcutaneous electrode assembly comprises: a first electrode comprising a first plurality of contacts configured for subcutaneous placement in a first region of a patient's face; And a second electrode comprising a second plurality of contacts configured for subdermal placement in a second region of the patient's face, wherein the first plurality of contacts and the second plurality of contacts are connected to a third nerve stimulation Adjacent to or in contact with at least two other branches of the trigeminal nerve in order to treat the neurological disease. At least two other branches of the trigeminal nerve are selected from the group consisting of the optic nerve, the ophthalmic nerve, the jaw nerve, the pulmonary hypertrophy and the pulmonary hypertrophy, the olfactory temporal nerve, the olfactory facial nerve, the nerve, .

In the following, a method for treating neurological diseases through trigeminal nerve stimulation is described. In one embodiment, the method includes implanting an electrode assembly into a patient, the electrode assembly comprising: a first electrode comprising a first plurality of contacts configured for subcutaneous placement in a first region of a patient's face; And a second electrode comprising a second plurality of contacts configured for subdermal placement in a second region of the patient's face, wherein the first plurality of contacts and the second plurality of contacts are connected to a third nerve stimulation Adjacent to or in contact with at least one prong of a trigeminal nerve to treat a neurological disease; And applying an electrical signal to the electrode assembly with specific operating parameters to treat a neurological disorder. In one embodiment, applying the electrical signal comprises applying an electrical signal at a frequency in the range of about 20 to 300 Hertz, a current of 0.05 to 5 mA, a pulse period equal to or less than 500 microseconds. In one embodiment, applying the electrical signal comprises applying an electrical signal at a frequency in the range of about 20 to 300 Hertz, a current of 0.05 to 2 mA, and a pulse period not exceeding 500 microseconds. In one embodiment, the neurological disease is selected from the group consisting of epilepsy and other seizure related disorders, acute or chronic brain disorders, chronic headache and migraine and related disorders, and movement disorders.

The following describes a system for providing trigeminal nerve stimulation to treat neurological disorders. In one embodiment, the system comprises: a pulse generator; And a subcutaneous electrode assembly, wherein the subcutaneous electrode assembly comprises: a first electrode comprising a first plurality of contacts configured for subcutaneous placement in a first region of a patient's face; And a second electrode comprising a second plurality of contacts configured for subdermal placement in a second region of the patient's face, wherein the first plurality of contacts and the second plurality of contacts are connected to a third nerve stimulation Adjacent to or in contact with at least one branch of the trigeminal nerve to treat the neurological disease. The system further includes a wire operatively connecting the pulse generator and the subcutaneous electrode assembly. In some embodiments, the at least one branch of the trigeminal nerve is selected from the group consisting of an eye nerve, an orbital nerve, a jaw nerve, a pulleys, a supraspinatus, a pulmonary nerve, a nasal nerve, a temporal nerves, an ankle facial nerve, ≪ / RTI >

In the following, a subcutaneous electrode assembly for providing a trigeminal nerve stimulation is described. In one embodiment, the subcutaneous electrode assembly comprises: a first electrode comprising a first single contact configured for subcutaneous placement in a first region of a patient's face; And a second electrode comprising a second single contact configured for subdermal placement in a second region of the patient's face wherein the first contact and the second contact are positioned in a third Adjacent to or in contact with at least one of the nerves of the nerve. In some embodiments, the at least one branch of the trigeminal nerve is selected from the group consisting of an optic nerve, an ophthalmic nerve, a chin nerve, a gluteal hypertrophy, a gluteal hypertrophy, a temporal ganglion, an olfactory facial nerve, .

The following describes a system for providing trigeminal nerve stimulation to treat neurological disorders. In one embodiment, the system comprises: a pulse generator; And a subcutaneous electrode assembly electrically connected to the pulse generator, wherein the subcutaneous electrode assembly comprises a first electrode comprising at least one contact configured for subcutaneous placement in a first region of the patient's face, Wherein the first electrode is configured to be implanted in proximity to, adjacent to or in contact with at least one of the prongs of the trigeminal nerve to treat a neurological disease by trigeminal nerve stimulation, the system being configured for minimal current penetration into the patient ' The at least one branch of the trigeminal nerve is selected from the group consisting of an eye nerve, an orbital nerve, a jaw nerve, a pulmonary hypertrophy, a pulmonary hypertrophy, an ankle temporal nerve, an ankle facial nerve, an ankle nerve, a nerve and an anterior temporal nerve . In some embodiments, the subcutaneous electrode assembly includes a second electrode comprising at least one contact configured for subdermal placement in a second region of the patient's face, wherein the second electrode is configured to be actuated by a trigeminal nerve stimulus At least one branch of the trigeminal nerve is at least one branch of the trigeminal nerve, at least one branch of the trigeminal nerve, at least one branch of the trigeminal nerve, at least one branch of the trigeminal nerve, Ankle temporal nerve, ankle facial nerve, osteolytic nerve, nasal nerve, and transient temporal nerve. In some embodiments, the first electrode and the second electrode are configured to be in proximity to, adjacent to or in contact with the same flank of the trigeminal nerve. In some embodiments, the first electrode and the second electrode are configured to be in proximity to, adjacent to, or in contact with other branches of the trigeminal nerve. In some embodiments, the system further comprises a wire for operably coupling the pulse generator and the subcutaneous electrode assembly. In some embodiments, the system further comprises an adjustment device configured to adjust the maximum charge balance output current to less than about 30-50 mA. The neurological diseases are selected from the group consisting of epilepsy, seizure related disorders, acute brain disorders, chronic brain disorders, chronic headache, migraine, diseases associated with headache and migraine, and movement disorders. In some embodiments, the pulse generator comprises applying an electrical signal at a frequency in the range of about 20 to 300 Hertz, a current of 0.05 to 5 mA, a pulse period equal to or less than 500 microseconds. In one embodiment, the step of applying the electrical signal comprises applying a pulse signal having a frequency in the range of about 20 to 300 Hertz, a pulse period in the range of 50 to 500 microseconds, an output current density not exceeding about 25 mA / cm < / Cm < 2 > at an output charge density.

In the following, a subcutaneous electrode assembly for providing a trigeminal nerve stimulation for treating a neurological disease is described. In some embodiments, the subcutaneous electrode assembly includes a first electrode comprising at least one contact configured for subcutaneous placement in a first region of a patient's face, wherein the first electrode is configured to be actuated by a trigeminal nerve stimulus Wherein the subcutaneous electrode assembly is configured to provide minimal current penetration into the patient's brain, wherein at least one of the trigeminal nerves is adapted to be implanted in proximity to, adjacent to or in contact with at least one of the trigeminal nerves to treat a neurological disorder, Is selected from the group consisting of the optic nerve, the orbital nerve, the jaw nerve, the pulleys, the supraspinatus, the ankle temporalis, the ankle facial nerve, the ankle nerve, the nerve and the temporal nerve. In some embodiments, the subcutaneous electrode assembly includes a second electrode comprising at least one contact configured for subdermal placement in a second region of the patient's face, wherein the second electrode is configured to be actuated by a trigeminal nerve stimulus At least one branch of the trigeminal nerve is at least one branch of the trigeminal nerve, at least one branch of the trigeminal nerve, at least one branch of the trigeminal nerve, at least one branch of the trigeminal nerve, Ankle temporal nerve, ankle facial nerve, osteolytic nerve, nasal nerve, and transient temporal nerve. In some embodiments, the first electrode and the second electrode are configured to be in proximity to, adjacent to or in contact with the same flank of the trigeminal nerve. In some embodiments, the first electrode and the second electrode are configured to be in proximity to, adjacent to, or in contact with other branches of the trigeminal nerve. The neurological diseases are selected from the group consisting of epilepsy, seizure related disorders, acute brain disorders, chronic brain disorders, chronic headache, migraine, diseases associated with headache and migraine, and movement disorders.

In the following, a method for treating neurological diseases through trigeminal nerve stimulation is described. In one embodiment, the method includes implanting an electrode assembly into a patient, the subcutaneous electrode assembly comprising a first electrode comprising at least one contact configured for subcutaneous placement in a first region of a patient's face, Wherein the first electrode is configured to implant near, adjacent, or in contact with at least one branch of the trigeminal nerve to treat a neurological disorder by trigeminal nerve stimulation, the system being configured for minimal current penetration into the patient ' s brain , At least one branch of said trigeminal nerve selected from the group consisting of eye nerves, ophthalmic nerves, cranial nerves, pulmonary hypertrophy, pulmonary hypertrophy, bony temporal nerves, osteopharyngeal nerve, oculomotor nerve, and cranial nerve -; And applying an electrical signal to the electrode assembly with specific operating parameters to treat a neurological disorder. In some embodiments, the subcutaneous electrode assembly includes a second electrode comprising at least one contact configured for subdermal placement in a second region of the patient's face, wherein the second electrode is configured to be actuated by a trigeminal nerve stimulus At least one branch of the trigeminal nerve is at least one branch of the trigeminal nerve, at least one branch of the trigeminal nerve, at least one branch of the trigeminal nerve, at least one branch of the trigeminal nerve, Ankle temporal nerve, ankle facial nerve, osteolytic nerve, nasal nerve, and transient temporal nerve. In some embodiments, applying the electrical signal comprises applying an electrical signal at a frequency in the range of about 20 to 300 Hertz, a current of 0.05 to 5 mA, a pulse period equal to or less than 500 microseconds. In some embodiments, applying the electrical signal comprises applying an electrical signal at a frequency in the range of about 20 to 300 Hertz, a current of 0.05 to 2 mA, and a pulse period not exceeding 500 microseconds. The neurological diseases are selected from the group consisting of epilepsy and other seizure related disorders, acute or chronic brain disorders, chronic headache and migraine and related diseases, and movement disorders.

The following describes a kit for providing trigeminal nerve stimulation for treating neurological diseases. In some embodiments, the kit comprises the subcutaneous electrode assembly disclosed herein; And instructions for implanting the electrode assembly into a patient to treat a neurological disorder. In some embodiments, the kit comprises a pulse generator; And instructions for applying an electrical signal to the electrode assembly to treat a neurological disorder.

An embodiment of the problem to be solved by the present invention is to provide a method for diagnosing and treating an orbital nerve, an ankle nerve, an ankle nerve, an ankle nerve, an ankle nerve, And to provide a system and apparatus configured to stimulate the skin or epidermal segments of the trigeminal nerve located in the face, including the jaw nerve. The present invention provides a method for treating neurological diseases using trigeminal nerve stimulation (TNS) using implantable and easy to use devices and systems as a minimal surgical procedure.

The construction and operation according to the present invention can be understood from the following description with reference to the accompanying drawings, in which:
FIGS. 1A and 1B are views showing the positions of several branches (nerves) of a trigeminal nerve and the positions of major holes in epidermal junctions of a trigeminal nerve;
2A illustrates a wear state of an embodiment of a trigeminal nerve stimulation system including a subcutaneous electrode assembly provided in accordance with aspects of the present invention;
FIG. 2B illustrates the subcutaneous electrode assembly of FIG. 2A, showing a multi-contact electrode; FIG.
Figure 3 illustrates another embodiment of a subcutaneous electrode assembly configured for stimulation of multiple nerve bundles to be used in the system of Figure 2A;
Figure 4 illustrates another embodiment of a subcutaneous electrode assembly configured for stimulation of a cranial nerve or ankle facial nerve bundles to be used in the system of Figure 2A;
Figure 5 is a plot of pilot study results of external trigeminal nerve stimulation ("TNS"); And
Figure 6 summarizes one embodiment of the current, charge, current density and charge density parameters for a subject exposed to transdermal stimulation of the orbital nerve.

The present invention relates to methods, devices and systems used to treat neurological diseases through stimulation of epidermal elements of the trigeminal nerve ("TNS"). Particularly, the epidermal junctions of the trigeminal nerve located outside the skull of the face, namely, the orbital nerve, the pulmonary nerve, the pulmonary tunic, the temporal nerve, the temporal nervous system, the olfactory nerve, the ankle facial nerve, Minimal invasive methods of stimulation of nerves (also referred to as epidermal trigeminal nerve) are disclosed herein. Systems and devices and their application methods configured for therapeutic stimulation of trigonal neurons, such as epidermal trigeminal nerves, are also disclosed. Skin nerves of the trigeminal nerve in the face include, but are not limited to, the trigeminal and trigeminal nerves, brain, isolated nucleus, dorsal nucleus and dorsal medial thalamus, brain and brainstem structures, including the cerebral cortex, and And provides an opportunity for minimally invasive methods to stimulate other structures that play a role in the disorders.

The systems, apparatus, and methods described herein may be used to treat a variety of neurological disorders, including but not limited to seizure disorders, headaches, migraine and related disorders, movement disorders, coma, Type of nerve stimulation. In particular, an implantable or subcutaneous electrode assembly and a system configured identically for trigeminal nerve stimulation are disclosed herein. As described in more detail below, the electrodes are not located within a nearly critical structure such as the brain or vagus nerve, carotid or jugular veins. The electrodes are also not directly or physically attached or fixed to the nerve (e.g., by suturing) (requiring intracranial surgery and spinal fluid leakage, infection, nerve damage and / or severe pain). Instead, the subcutaneous electrodes (or electrode assemblies) attach to the periosteum or skull membrane (the membrane that is the outer surface boundary of the skull) and under the epidermis (the outermost layer of skin) ) Adjacent to, or in contact with, or near the area of the patient's face or skull. The nerves are stimulated with operating parameters within a limited range to minimize current penetration into the brain and are determined by factors such as patient history, disorder to treat, or personal sensitivity to stimulation. The placement of the electrode assembly described herein does not require intracranial surgery (ie, implantation under the skull), thus reducing the risk of spinal fluid leakage and infection. In some embodiments, the electrode assembly will be positioned or configured to stimulate smaller branches of the trigeminal nerve. That is, the electrode assembly is located away from the main branch of the brain and nerve. Surprisingly, placing the electrode assembly away from the main branches of the brain and nerves is believed to be as effective as attaching directly to the nerve branch, which will increase patient safety.

In some clinical situations, brain stimulation, such as electroconvulsive therapy (ECT) and continuous cranial magnetic stimulation therapy (rTMS) for psychiatric measures, has been found to have undergone sufficient clinical endorsement approved by the US Food and Drug Administration. Some brain stimulation methods generate currents in a large volume of the cortex and cause the brain to become a bulk conductor, such as, for example, ECT to the frontal level, rTMS to a large regional level (i.e., the cortex of the entire dorsal frontal lobe) As well as to treat them. In addition, in-depth brain stimulation is based on small stimuli, and local volumes cause discharge in a large number of cells. The systems, devices and methods of the present invention send minimal current to the brain and signals are sent to the brain to control the activity of the associated neuroanatomical structures. Without being bound by any particular theory, electrical pulses generate signals in the dermal nerves of the trigeminal nerve, and the electric fields are confined to the skin tissue and thus leakage into the brain is minimized. These electrical pulses trigger a cascade of changes in the neuronal signal that involves a very limited and precise replenishment of specific networks of neurons. Neuroanatomical pathways enable the goal control of activity in areas accompanied by depressions (cerebral, anterior, cerebral, and cortical). Thus, the systems, apparatus, and methods disclosed herein utilize the existing infrastructure of the brain to transmit signals to targets of interest. In the context of this disclosure, minimum current penetration is determined by (1) the charge density of about 0 uC / cm2 in the cerebral cortex, or (2) the calculated and measured, or the following thresholds in the cerebral cortex: (a) Current density, charge density, or equivalent charge, which causes the activation of the electrodes; And (b) a charge density of less than 10 uC / cm 2 in this example and a charge density of 0.001 to 0.1 uC / cm 2 in other embodiments, and a charge density not known to cause brain damage, and Means a calculated, measured or modeled charge density less than a combination of equivalent charges. In some embodiments, the low charge density will be used when the individual patient's cerebral nervous system is sensitive enough to be at a low level (a level that allows the clinical benefit to accumulate).

The following description is presented to enable those skilled in the art to make and use the art to which the present invention pertains and discloses the various aspects of the disclosure as the best mode by which the inventor undertakes. However, various modifications will be apparent to those skilled in the art, and the principles of the technical subject will now be described in terms of: (1) methods of treating neurological diseases by trigeminal nerve stimulation, (2) Configured system and implantable electrode assembly, and (3) methods for treating neurological diseases using such devices and electrode assemblies.

For discussion relating to the trigeminal nerve, reference is made to FIGS. 1A and 1B, which show the location of several branches of the trigeminal nerve and the location of the main hole to epidermal junctions of the trigeminal nerve. The trigeminal nerve is a maximum of twelve pairs of cranial nerves and has extensive connections to the brain stem and other brain structures. The trigeminal nerve (often categorized as the fifth cranial nerve, cranial nerve V or CN V) has three main divisions, and its cervical branches are both bidirectional and highly accessible. The orbital nerve or eye nerves are often referred to as the V1 segment, and this segmentation also includes a pulley elevation and a pulley. The maxillary nerve is referred to as the V2 segment, and this segment includes the anterior facial nerve and the subtalar nerve. The jaw tip of the mandibular nerve is referred to as the V3 segment, and this segment also includes the cranial nerve. Orbital nerves provide sensory information about the forehead, upper eyelid, nose and eye. Anwachela branch provides sensory information about the lower eyelid, the ball and the upper lip. The jaw tip provides sensory information about the skin and lips of the lower face (ie, jaw and tongue). These branches exit the skull through the three holes as shown in Figures 1A and 1B. The orbital nerve or eye nerve is located in hole 1 at about 2.1 to 2.6 cm from the midline of the nose (in adults) and is located just above the bone around the eye hole located below the eyebrows. The orbital nerve or maxillary nerve is present in hole 2 at about 2.4 to 3.0 cm from the midline of the nose (in adults) and the jaw nerve is present in hole 3 at about 2.0 to 2.3 cm from the midline of the nose (in adults) do. The nerve is the division of the eye nerve. Other sensory segments, including the ankle facial nerve, the osteochondral nerve, the ankle temporal nerve, and the cranial nerves, are derived from other holes.

The fibers from the three major branches are joined together to form the trigeminal ganglion. From there, the fibers ascend into the brainstem at the height of the pons, ascend to the synapse by the spinal nucleus of the pons and the spinal nucleus of the CN V. The fibers descend from the spinal nucleus and spinal cord of V, descend into the inner nuclear nucleus (VPM) of the thalamus, and protrude into the cerebral cortex. Sensory fibers of light touch are fibers with large bone marrow, go up to the nucleus of the posterior nucleus of the thalamus, and protrude into the brain cortex.

The trigonal nuclei are isolated from others and have protrusions leading to nucleus (NTS) and other brain structures, including the brain. NTS accepts afferent nerves from vagus and trigeminal nerves. The NTS integrates inputs from multiple sources, including the brain and protrudes into the brainstem and forehead structures. It is a paired nuclear structure in the thoracic pontine, located just below the floor of the fourth ventricle. It has a wide range of axons in the brain stem, subcortical and cortical structures, and is an important part of the embryo activation system. The brain is a key part of the pathway activated by the brainstem noradrenaline, and produces the neurotransmitter norphe- nephrine. Norepinephrine plays a role in attention, agility, blood pressure and heart rate control, anxiety and mood.

Although not based on a particular theory, in some embodiments, the connections between the nucleus, the thalamus, and the cerebral cortex in isolation with the trigeminal nerve, cerebral cortex, neural nucleus and nerve are well known to those skilled in the art It may be related to the potential role of the trigeminal nerve in many neurological disorders, including brain injury, seizure disorders, headaches, migraine and movement disorders. Therefore, subcutaneous stimulation of the trigeminal nerve under customization and parameters may be effective in the treatment of multiple neurological disorders.

Neurological diseases

Coma and vegetative states. Subcutaneous nerve stimulation will improve the person's consciousness in coma and vegetative state. Although not based on any particular theory, the Brain Intergenome Activation System (including the child) and thalamus play a role in activation of agility, awareness, and higher cortical structures. This stimulation of the brain structure and other brain structures can enhance recovery of cognition and motor function after various forms of brain injury, as well as restoration of consciousness in the coma, to the trigeminal nerve and nucleus projection. Given the protrusions of the trigeminal nerves into the core brainstem, thalamus, and cortical structures involved in awareness and consciousness, the trigeminal nerve represents one way to activate this core structure.

Migraine. Although not based on a particular theory, headaches and migraines are associated with pathways connected to the trigeminal nerve. Activation of certain trigonal neural structures and pathways plays a role in headache (Nature Medicine 2002; 8: 136-142). In the flexible brain covering the cerebral cortex, the afferent trigeminal nerve fibers from the vascular structure are activated, activating or sensitizing the trigeminal nerve ganglion and myocardial nerve nucleus, which in turn activates the superficial salivary nucleus and the ganglion ganglion (Nature Medicine 2002; 8: 136-142). From these structures, the protrusions leading to the blood vessels in the dura mater cause the release of vasoactive peptides, protein eruption and activation of the nitric acid pathway, resulting in dilatation of the epidural blood vessels and eventually headaches. This is often referred to as a trigeminal nerve vaginal reflex, which will be a mechanism in the origin of migraine (Nature Medicine 2002; 8: 136-142). Though not based on a particular theory, surgically creating a lesion or blocking the trigeminal nerve would inhibit this response, resulting in a reduction of events involving migraine and other headache syndromes. As described herein, the acute or chronic electrical stimulation of the trigeminal nerve through the facial nerve or epidermal junctions under the frequency of interruption of the circuit described above modulates this trigeminal nerve vascular response, Reduce or stop the occurrence of headaches or migraines.

Movement disorder

Movement disorders are characterized by unwanted movement of the body and include, but are not limited to, complicated movements such as tremor, convulsions and seizures, unwanted increases in tone of muscles, such as tension disorders, movement disorders, and chorea . Though not based on any particular theory, we believe that TNS will regulate activity in key structures involving movement disorders, including, but not limited to, the following: the sagittal, basal ganglia, brain stem and cerebral cortex, Hypothesis that it would inhibit abnormal neuronal activity in the motor system (which would cause this unwanted phenomenon).

Spastic and other movement disorders

Many drugs that work on dopaminergic neurons in the brain are responsible for inducing unwanted movement. This has been demonstrated for the treatment of Parkinson's disease with levodopa for the use of neuroleptic agents in psychosis, manic depression and other conditions (Damier, Curr Opin Neurol 22: 394-399, 2009) and for gastrointestinal symptoms (Rao and Camilleri, Pharmacol Ther 31: 11-19. 2010). Some people suffer from movement disorders due to genetic problems (Coubes et al., Lancet 355: 2220-1, 2000). These dysmorphic syndromes consist of undesired movements that can begin with the tongue, lips, mouth, or facial muscles and can be transmitted to other parts of the body. The exact mechanism by which this movement disorder occurs is unclear, but the surgical treatment of the thalamus and the dorsal root in places where deep brain stimulation can lead to improvement (Kupsch et al., J Neurol 250 Suppl 1: 147-152 2003) Complex. Though not based on any particular theory, the trigeminal nerve, the connections between the nucleus and the nucleus, and the nucleus, and the connections between the thalamus, activate this core structure, thus providing a mechanism whereby trigeminal nerve stimulation can improve symptoms of movement disorders.

Seizure disorder

Though not based on any particular theory, trigeminal nerve stimulation will modulate activity in the brain, brain stem, thalamus, and cortex, and will activate inhibition mechanisms and pathways that affect the neuron's polarity. The trigeminal nerve stimulation also inhibits the paired polar mechanism and pathway, eventually inhibiting epileptic seizures and cortical and subcortical spread. This process will directly or indirectly affect the activity level by focusing on the epilepsy itself.

Thus, as described herein, stimulation of epidermal or cutaneous branches of the trigeminal nerve provides a minimally invasive neural coordination option. In addition, the stimulation parameters can be tailored according to each condition, and the brain stem, thalamus or cortical structures involved in each state can be activated or inhibited depending on the pathology physiology of the condition being treated.

For discussion of some embodiments of methods, systems, and devices for using implantable electrodes according to aspects of the present invention, reference is made to Figs. 2A-4, which illustrate the use of these electrodes for subcutaneous stimulation of epidermal junctions of the trigeminal nerve System and apparatus and methods of use thereof.

According to one aspect of the present invention, a method of treating a neurological disorder using a trigeminal nerve stimulus ("TNS") is provided. In some embodiments, the method for treating such neuronal disease by stimulating epidermal junctions of the trigeminal nerve comprises contacting the at least one of the triple-hole or epidermal junctions of the trigeminal nerve with the face, (See FIGS. 1A and 1B), and stimulating the electrodes using a pulse generator for a certain time with specific operating parameters. Because electrode assemblies are attached or fixed to subcutaneous tissue or connective tissue located on the periosteum or cranial membrane and below the epidermis in order to position the electrodes close to, adjacent to, or in contact with the target nerve branch, electrode assembly placement requires intracranial surgery I never do that. In some embodiments, the electrode assembly will be configured to stimulate small branches of the trigeminal nerve. Surprisingly, placing the electrode assembly away from the main branches of the brain and nerves is believed to be as effective as attaching directly to the nerve branch or through other contacts, which will increase patient safety.

In one embodiment, the unidirectional or bi-directional stimulation of the trigeminal nerve can be achieved by placing a single electrode or separate electrodes on the right and / or left side, so that the implanted electrodes are positioned adjacent to the orbital or optic nerve pores (Figures 1A and 1B, hole 1). In some embodiments, the electrode assembly is configured for bi-directional stimulation. In some embodiments, since the function of other brain structures is not the same on the right and left sides (i.e., linguistic expressions are most commonly concentrated in the language center in the left hemisphere, While damage to the corresponding region in the right hemisphere does not result in loss of this function but changes clever functions), the bidirectional stimulus will provide similar or better efficacy than the one-way stimulus. Synergistic effects will also occur in bidirectional stimulation.

In some embodiments, two separate electrodes can be implanted in the soft tissue of the patient's forehead, with each electrode located near the foramen of the eye nerve or near the eye opening. In other embodiments, the implanted / sparable electrode (s) may be positioned adjacent, in close proximity to, or in contact with the anterior and posterior nerves (Figs. 1A and 1B, hole 2) or the chin nerve (Figs. 1A and 1B, have. In other embodiments, the electrodes are positioned adjacent, in close proximity to, or in contact with the pulmonary nerve, pulmonary, temporal, temporal, or auditory nerves, nasal and / . The unidirectional stimulation of the trigeminal nerve and the bi-directional stimulation can be accomplished by placing single or separate electrodes on the right and / or left side of the face so as to unilaterally stimulate near at least one epidermal hole of the trigeminal nerve. In other embodiments, the electrodes will be implanted over a number of epidermal holes in the face to stimulate other trigeminal nerves simultaneously or asynchronously. In other embodiments, the stimulus will be made in the zones of the skin of the fingernails of the trigeminal nerve without attachment to the nerves.

2A and 2B, and with reference to FIGS. 3 and 4, in one embodiment, a system 10 for treating neurological disorders and conditions through the subcutaneous TNS comprises an implantable subcutaneous electrode assembly (20), a pulse generator (30) and an electric cable or wire (40) to be placed under the skin.

The pulse generator 30 will be one of a variety of suitable stimulus and signal generators. In some embodiments, the pulse generator 30 will include electronic circuitry for receiving data and / or power from the outside of the body by induction, radio frequency (RF), or electromagnetic coupling. In some embodiments, the electronic circuitry includes an inductive coil for receiving and transmitting RF data and / or power, an integrated circuit (IC) chip for decoding and transmitting stimulation parameters and generating stimulation pulses, Such as capacitors, resistors, transistors, coils, and the like, which are necessary to make the transistors in the array.

In other embodiments, the pulse generator 30 will include a programmable memory for storing a set of data, stimulus, and control parameters. Among other things, the memory allows the stimulation and control parameters to be adjusted to an effective and safe setting to minimize patient discomfort. Specific parameters will provide therapeutic advantages for various neurological diseases. For example, some patients respond to intermittent stimuli, while others require continuous stimuli to treat their symptoms.

In some embodiments, the implantable pulse generator 30 will include a power source and / or a power storage device. Possible options for supplying power to the system include, but are not limited to, an external power source connected to the pulse generator 30 via, for example, an RF link, a suitable means for generating or storing energy A self-contained power source that uses a self-contained power source, such as a primary battery, a replenishable or rechargeable battery such as a lithium ion battery, an electrolytic capacitor, a supercapacitor, a kinetic energy generator, etc.) (E. G., An RF link, an optical link, a thermal link, an inductive link or other energy coupling link) of the power source.

In some embodiments, the pulse generator 30 operates independently. In other embodiments, the pulse generator 30 cooperates with other implanted devices or other devices external to the patient ' s body. For example, the pulse generator may communicate with other implanted pulse generators, neurostimulators, other implanted devices, and / or devices external to the patient's body via RF links, ultrasound links, thermal links, will be. In particular, the pulse generator will communicate with an external remote control (e.g., a patient and / or pseudo-programmer) that can send commands and / or data to the pulse generator and receive commands and / or data from the pulse generator.

In some embodiments, the system includes a conditioning device. The regulator is configured to be attached to the pulse generator 15 and is configured to provide a maximum charge balance output current of less than about 30 to 50 mA to minimize the penetration of current to the brain to increase patient tolerance. The conditioning device may be configured to adjust the surface area, placement and orientation of the electrode, whether the electrode stimulates near or near the skull or away from the skull (i.e., the jaw tip), 0.25 to 5.0, 0 to 10, 0 to 15 Lt; RTI ID = 0.0 > of < / RTI > Current The TENS unit stimulates with a maximum output current of up to 100mA, penetrating the skull and causing currents that the patient can not tolerate.

In one embodiment, an electrical cable or wire 40 is configured to provide a physical and electrical link between the pulse generator 30 and the electrode assembly 20. In other embodiments, the pulse generator 30 and the electrode assembly 20 communicate wirelessly (i.e., the wire 40 is not used). System 10 and / or electrode assembly 20 become part of the kit. In some embodiments, the kit also includes instructions for treating a neurological disorder or condition according to the symptoms described herein.

In one embodiment, as shown in Figure 2A, the electrode assembly 20 described in the illustrated embodiment is referred to as both orbital electrodes. The electrode assembly 20 may be connected to an implanted / implantable pulse generator by electrical cables 40. Alternatively, the electrodes may be connected wirelessly with an external pulse generator and deliver energy across the skin by an inductive connection between the coil implanted in the patient and the coil in an external pulse generator (not shown).

As shown in Figure 2B, in one embodiment, the implantable or subcutaneous electrode assembly 20 will comprise a set of multi-contact electrodes 20a, 20b configured for bidirectional simultaneous and asynchronous stimulation of the optic nerve . The multi-contact electrodes 20a and 20b of the subcutaneous electrode assembly 20 include a first pair of contacts 112a and 112b for implantation in a first region of the patient's face, such as the right or left side of the patient's face An electrode, and an electrode comprising a second pair of contacts 112a, 112b for implantation in a second region of the patient's face, such as the left forehead or the left side of the patient's face. In other embodiments, the first and second regions of the patient's face will lie on the same side of the face corresponding to different nerves, holes, and the like, respectively. For example, the first region corresponds to the orbital nerve and the second region corresponds to the orbital nerve. The electrode assembly 20 will include a plurality of isolation regions 116 configured to isolate the isolation region 116 or respective electrode contacts. The first pair of contacts include a first upper contact 112a and a first lower contact 112b while the second pair of contacts include a second upper contact 112c and a second lower contact 112d do. The electrode assembly 20 includes four electrodes for biasing the stimulation pulses to the nerves. Although the electrode assembly 20 shown in Figure 2B is shown as having only a pair of electrical contacts 112a / b, 112c / d, in other embodiments, each electrode 20a, Small contacts will be provided.

3, the electrode assembly 20 will include a multi-contact electrode 20c having a plurality of contacts 112 and a plurality of isolation regions 116. In some embodiments, The electrode assembly of FIG. 3 is configured to stimulate both the orbital elevation and the orbital nerve in one direction. In other embodiments, the electrode assembly will comprise a plurality of multi-contact electrodes comprising a plurality of contacts and a plurality of insulating regions. In various embodiments, the geometry or layout of the electrode assembly will be a linear electrode, where the linear electrode may be a single contact or a series or multiple conductive contacts and insulating spaces or flats, a "ribbon & "Electrode and also has a plurality of one or more conductive regions and isolation regions on the surface.

4 shows another embodiment of the electrode assembly 20 used in the system 200. As shown in FIG. 4, the electrode assembly 20 will include a multi-contact electrode 20d having a plurality of contacts 112 and a plurality of isolation regions 116. In some embodiments, The electrode assembly of FIG. 4 is configured to stimulate at least one of the anterior temporal nerve and the apophyseal facial nerve in one direction. In other embodiments, the electrode assembly 20d is configured to stimulate both the anterior temporal nerve and the apophyseal facial nerve. 4, in one embodiment, the electrode assembly will be implanted in one direction. The electrode assembly is configured to be located at, near, or above the epidermal hole in the face and may be configured to simultaneously and / or asynchronously receive one or more other tertiary nerves (e.g., the temporal nerve and / ≪ / RTI > In other embodiments, the electrode assembly will be bi-directionally implanted to stimulate the target nerve on both sides of the patient's face.

Those skilled in the art will appreciate that various applications and variations of the above-described embodiments of the electrode assembly 20 are within the scope and spirit of the present invention. For example, one embodiment of an apparatus according to the present invention includes a unidirectional electrode assembly configured for unidirectional stimulation of the optic nerve (see FIG. 3). In other embodiments, the implantable electrode assembly will be configured for stimulation of the orbital nerve or jaw nerve. In other embodiments, the electrode assembly is configured for simultaneous or asynchronous stimulation of multiple elements of the trigeminal nerve in one or both directions. In other embodiments, external, transcutaneous electrodes and implanted subcutaneous electrodes are used to stimulate one or more branches of the trigeminal nerve simultaneously or asynchronously. An example of an external, transdermal electrode assembly is disclosed in U. S. Patent Application Serial No. < RTI ID = 0.0 > (USSR) < / RTI > filed on the same date as the present application and identified by attorney docket number 001659-5001-US as "SYSTEMS, DEVICES AND METHOD FOR THE TREATMENT OF NEUROLOGICAL DISORDERS AND CONDITIONS" For example, in Patent Application No. ___________ [2007-292-2], which is hereby incorporated by reference.

For ease of understanding, the remaining discussion is made with reference to FIG. 2B. However, it should be understood that the disclosure is not limited to embodiments having multiple contacts, a single multi-contact electrode having a single contact electrode, embodiments involving multiple multi-contact electrodes having multiple contacts, implementation configured for unilateral or bilateral stimulation Examples and other embodiments falling within the spirit and scope of the invention.

As can be understood from FIG. 2B, the electrode assembly 20 is configured to simultaneously stimulate both the right and left eye nerves simultaneously or asynchronously. The placement of the first implanted electrode contact pairs 112a and 112b and the second pair of electrode contacts 112c and 112d on opposing sides of the nose midline may cause the stimulation current to move in a positive direction, To move in the direction of the nerve. In addition, as the response to stimulation is localized and thus varies from one side of the midline to the other, this configuration of the electrode assembly 20 allows the electrode contact pairs 112a, 112b and 112c, And / or unilaterally stimulated. Depending on the position of the pulse generator, in some embodiments, the electrodes and / or their connectors (i.e., the wires 40) are longer than 150 mm and the orbital, orbital, and / or jaw- . Other branches, short electrode / connector lengths are preferably dependent on the placement of the pulse generator.

In stimulation when unidirectional electrical pulses are generated, the upper electrode contacts 112a, 112c and lower contacts 112b, 112d have fixed polarities. In stimulation when unidirectional electrical pulses are generated, the upper electrode contacts 112a, 112c and lower contacts 112b, 112d have fixed polarities. In stimulation when electrical pulses of alternating polarities are generated, the upper electrode contacts 112a, 112c and lower contacts 112b, 112d have alternating polarities.

Each of the contacts 112a, 112b, 112c and 112d is configured to carry electrical pulses with minimal potential for damage to the scalp tissue due to excessive charge accumulation and with minimal potential for current penetration through the inner surface of the skull. The distance between the first implanted electrode contact pair 112a, 112b and the second electrode contact pair 112c, 112d is configured to stimulate the eye nerve while minimizing current transport to the surface of the brain. The electrode size and the inter-electrode distance of the electrode arrangement will vary for children, adults, men and women depending on the dimensions of the individual's body.

The electrode assembly 20, and in particular the contacts 112a, 112b, 112c and 112d, may be made of a material selected from the group consisting of tantalum, titanium nitride, platinum, iridium, tantalum, Niobium, rhenium, palladium, gold, nichrome, stainless steel or alloys thereof. Other compounds of implantable electrodes will be apparent to those skilled in the art.

In various embodiments, the distance between contacts 112a and 112b and the distance between contacts 112c and 112d may be 0.1 cm, 0.5 cm, 1 cm, 2 cm, 3 cm, 4 cm, 5 cm, 6 cm, 7 cm, 8 cm, 9 cm, , ≪ / RTI > and / or less than or equal to one or more of < / RTI > One skilled in the art will appreciate that one or more of these distances may be used as a boundary of a range of distances.

In some embodiments, the sense electrodes will be included in the electrode assembly to monitor physiological parameters, such as data of an EEG recording device, and allow the feedback device to adjust the stimulation parameters to stimulation parameters So that it can be adjusted appropriately. In some embodiments, the sensing electrode is one of the stimulating electrodes and is used for sensing during the "off" portion of the duty cycle. In some embodiments, the sensing electrode is an additional electrode, and is used only for sensing.

2B, the electrode assembly includes two implanted electrodes positioned adjacent to the orbital hole of the patient 5 and is positioned over the orbital ridge approximately 2.1 to 2.6 cm laterally to the nasal midline . The ends 13a and 13b of the electrodes 20a and 20b are located at points where electrodes 20a and 20b are connected to leads (not shown) for carrying an electrical stimulus coming from a pulse generator (not shown) . The pulse generator itself may be placed at various locations below the skin or under the scalp, such as the pectoral muscle in the back of the neck, and the lead wires are located under the patient's skin to connect thereto. In other embodiments, the pulse generator will be externally positioned as it would be attached to the patient's clothing.

In some embodiments, as in the embodiment shown in FIGS. 2A and 2B, the nerve stimulation can be performed in the following exemplary setting: for at least one hour per day, at a frequency in the range of about 20 to 150 Hz, in a range of about 0.05 to 20 mA , A pulse period in the range of about 50 to 250 milliseconds, and a duty cycle of 10% to 50%. For optimum patient comfort and low power consumption, stimulation parameters at the lower end of these ranges would be desirable. In other embodiments, other values of operating parameters will be used, as described in more detail below. In other embodiments, a single implant electrode will be used.

3, in one embodiment, the electrode assembly will be implanted in one direction. The electrode assembly will be configured to stimulate one nerve disorder. For example, as shown in FIG. 3, the electrode assembly may be placed on or near a number of epidermal perforations in the face, or adjacent thereto, and may be stimulated simultaneously or asynchronously with other trigeminal nerves (oropharyngeal and orbital nerves) .

As best seen in Figures 2A and 2B, in one embodiment, the electrode assembly 20 is implanted in the soft tissue of the forehead of the patient 5. The electrode assembly 20 is connected to the implanted pulse generator 30 via implanted electrical cables 40 located at or below the patient ' s skin. In the illustrated embodiment, the stimulus via the pulse generator 30 is routed through electrical cables 40. In other embodiments, electrical stimulation may be performed wirelessly, using an external, non-implanted pulse generator that uses an inductive connection to carry energy to the implanted electrode assembly 20. In other embodiments, the electrode assembly may be connected to the external pulse generator through a wire or wirelessly.

Stimulation is performed under operating parameters as described herein. In some embodiments, the values of the operating parameters are within a range that results in minimal current penetration into the brain, and the stimulus, such as tingling of the mild symptoms across the forehead, scalp, or teeth, without the patient feeling significant inconvenience or pain It will be chosen to experience the feeling. These values will vary depending on the therapeutic purpose.

According to one aspect of the present invention, there is provided a method for treating a neurological disease using the electrode assembly 20 as described above. In one embodiment, the method for treating the neurological disease includes implanting the electrode assembly 20 under the skin (e. G., The patient's forehead), implanting the electrode assembly 20 into the implanted pulse generator 30 , And stimulating the electrode assembly 20 under defined values of operating parameters. In one embodiment, the bidirectional orbital electrode 20 shown in Figures 2A-2B has a frequency in the range of about 20 to 300 Hz, a pulse period in the range of 50 to 250 microseconds (μsec), at least 30 minutes to 1 hour While the output current in the cerebral cortex is less than 10mA. In some cases, the stimulation may be provided for less than 30 minutes per day, or may be provided for 24 hours per day.

Accepted standards for safe stimulation will be incorporated for chronic stimulation. The parameters may be selected or calculated to carry a stimulus to the surface of the brain that carries no stimulus or negligible stimulus. Safety parameters currently accepted for chronic stimulation are below the charge equivalent to above 20 μC / ㎠ at the surface of the brain. Generally, for a given region of the surface of the brain, the accumulative charge above is due to all electrode contacts not exceeding this threshold, and the parameters do not carry a stimulus to the surface of the brain or carry a negligible stimulus , While it is sufficient to stimulate the nerves described here.

According to one aspect of the invention, a method of treating a neurological disease by a TNS comprises selecting an optimal value of an operational parameter for each patient ' s stimulation. In one embodiment, the values of the operating parameters will be selected so that the patient experiences a stimulus feeling such as a tingling of the mild symptoms across the forehead, scalp or face without feeling significant discomfort or pain. In some embodiments, low currents (e.g., 0.05 to 5 mA) and careful electrode placement will be selected to avoid restoring the nerves that provide pain sensation to the teeth. In some embodiments, low currents (e.g., 0.05 to 5 mA) will be selected so that current is prevented from penetrating into the skull and brain, particularly at the orbital nerve location.

 In one embodiment, a method of selecting operating parameters comprises evaluating variables such as pulse period, electrode current, duty cycle and excitation frequency, wherein the operating parameters are selected from the group consisting of Are selected to ensure that the total charge, charge density, and stomatal equivalent charge are within the accepted safety limits for the scalp, facial tissue, nerve, and brain, while preventing or minimizing current penetration. In addition, in some embodiments, the selection of electrical stimulation parameters, electrode design, and inter-electrode distance may be achieved by preventing or minimizing current penetration under the bone tissue of the scalp, while electrically stimulating the area of the epidermal elements of the trigeminal nerve About 3 to 4 mm deep).

In various embodiments, the stimulation parameters carried by the implanted pulse generator are determined (programmed) when the device is implanted surgically. In other embodiments, these parameters are altered or adjusted or otherwise programmed by an external device. These external programming elements communicate wirelessly with the implanted components. This may be done, for example, by radio frequency signals, inductive coupling, or other means apparent to those skilled in the art.

In various embodiments, the stimulus is carried under a range of specific pulse widths or pulse widths. The stimulus is set to deliver pulse widths in a range greater than, equal to, and / or less than at least one or more of 50μs, 60μs, 70μs, 80μs, 90μs, 100μs, 125μs, 150μs, 175μs, 200μs, 225μs, 250μs, . One skilled in the art will appreciate that one or more of these times may be used as the boundary of the pulse width range.

In some embodiments, the stimulus amplitude is delivered as a controlled voltage or current stimulus. In other embodiments, it may be delivered as a capacitive discharge. In various embodiments, the current amplitudes can be in a range of a lower limit of about 300 A and an upper limit of about 30 mA to 35 mA, depending on the surface area of the electrodes, the distance between the electrodes, the excited branch (s), and the modeling data as described above . In some embodiments, the current used will be in the range of 0.1mA to 10mA. In other embodiments, the current used will be in the range of 0.1 mA to 3 mA. In various embodiments, the amplitudes are 50 μA, 75 μA, 100 μA, 125 μA, 150 μA, 175 μA, 200 μA, 225 μA, 250 μA, 275 μA, 300 μA, 325 μA, 350 μA, 375 μA, 400 μA, 425 μA, 450 μA, 475 μA, 500 μA, 525 μA, 550 μA , 575 μA, 600 μA, 625 μA, 650 μA, 675 μA, 700 μA, 725 μA, 850 μA, 875 μA, 900 μA, 925 μA, 950 μA, 975 μA, 1 mA, 2 mA, 3 mA, 4 mA, 5 mA, 6 mA, 7 mA, 8 mA, 9 mA, Greater than or equal to one or more, and / or within a smaller range. One skilled in the art will appreciate that one or more of the above amplitudes may be used as the boundary of the amplitude range. The current will be carried constantly or intermittently.

In some embodiments, treatment under a given current amplitude can be performed in a patient with an acceptable limit of charge density and a significant equivalent charge (e.g., <20 μC / cm 2 / phase, Exp Neurol 1983; 79: 397-411) It is provided to minimize or eliminate current propagation to the cerebral cortex, ensuring that it is adhered to for safety. Although there is no theoretical background, it is believed that the use of multi-contact electrodes as described herein will occur even when very low charge densities are employed, as more fibers in the nerves are involved in the nerve stimulation process.

In various embodiments, the stimulus may be delivered within one or more frequency or frequency ranges. This stimulus may be set to be delivered at a frequency that is less than, equal to, and / or greater than one or more of 50 Hz, 45 Hz, 40 Hz, 35 Hz, 30 Hz, 25 Hz, 20 Hz, 15 Hz, or 10 Hz. In various embodiments, the stimulus is at a frequency greater than or equal to one or more of 20 Hz, 30 Hz, 40 Hz, 50 Hz, 60 Hz, 70 Hz, 80 Hz, 90 Hz, 100 Hz, 125 Hz, 150 Hz, Can be set to be transmitted. One skilled in the art will appreciate that one or more of the above frequencies may be used as a boundary of the frequency range.

In various embodiments, the stimulus may be delivered under a specific duty cycle or a range of duty cycles. These stimuli are 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% , 85%, 90%, 95%, or 100%, and / or in a range of less than or equal to one or more of the following: In some embodiments, those skilled in the art will appreciate that one or more of the foregoing percentages may be used as a boundary of the duty cycle range.

In some embodiments, the external device is used by the implanted electrode assembly described herein to differentiate the location of the branches or branches of the trigeminal nerve to be targeted with a stimulus for each patient. An external device is used to map and target the desired branches or branches of the trigeminal nerve and will be used to identify the optimal stimulation parameters in terms of efficiency and safety. In one embodiment, the apparatus will comprise a plurality of external (transdermal) TNS electrodes. The doctor estimates the position of the target branch and attaches the electrodes to the patient's skin above the target location. The stimulus will be applied and the actual position of the target branching or branching or the desired (optimal) stimulation position will be determined. Stimulation parameters will also be set. Once the location and / or excitation parameters are set via the external device, the data will be used to assist in guiding the placement of the implanted electrodes of the individual patient and to set customized stimulation parameters for the patient.

In addition, using external electrodes for the stimulation of the trigeminal nerve, in addition to parameters of stimulation based on optimal specific locations and individual versus individual diversity, distinguishes those who are likely to benefit from such minimally invasive systems can do. Various neurological diagnostic, imaging, or dermal neural mapping methods may describe differences in the patient's body to optimize stimulation for efficiency and / or safety. The use of such a minimally invasive system also allows the examination and identification of patients who are likely to benefit from other implantable systems, such as deep brain stimulation. This can be conceptualized as three solutions as stage I (external TNS of the trigeminal nerve), stage II (transplantation of the tertiary nerves TNS), and stage III (deep brain stimulation). Stage I can be checked against Stage II, and Stage II can be checked against Stage III. By monitoring the patient to find evidence of a beneficial therapeutic effect, such as a reduction in the severity of the symptoms, the treatment results at one level will be used to determine if the outcome of the treatment with the invasive method from above is effective.

Methods for assessing the use of trigeminal nerve stimulation to treat a patient &apos; s neurological disease are described herein. The method includes the steps of applying a transcutaneous system to provide a patient with trigeminal nerve impulses, monitoring the patient for evidence of an ability to withstand TNS therapy or evidence of a useful therapeutic response, Providing an electrode assembly or system, and implanting a subcutaneous electrode assembly or system into the patient for treatment of a neurological disorder.

Methods for assessing the use of deep brain stimulation to treat a patient &apos; s neurological disease are described herein. The method includes applying a transcutaneous system to provide a patient with a trigeminal nerve stimulation and monitoring the patient for at least one of evidence of patient tolerance or useful therapeutic response to TNS therapy, Implanting a transdermal electrode assembly as described herein to a patient for treatment of a neurological disorder, implanting a transdermal electrode assembly as described herein, treating the implanted device with patient tolerance or a useful therapeutic response Monitoring the patient for at least one to generate an extracellular metric, and analyzing the external and extracellular metrics to determine whether the patient is benefiting from deep brain stimulation.

The following examples are given to illustrate the clinical benefits of trigeminal nerve stimulation and to clarify the subject matter of this specification without imposing any limit to the scope of the present invention. In Example 1, patients with epilepsy were treated with TNS using exotropes. In Example 2, the patient was treated using transdermal electrodes for both wrist stimulation.

Example  One

Figure 5 shows the results from a pilot phase study of external trigeminal nerve stimulation. Subjects were enrolled in this study for patients with epilepsy that met criteria for inclusion or exclusion for feasibility studies. Patients participated in the baseline period of 1 month of seizure frequency, followed by active irritation of the trigeminal nerve or of the ophthalmic nerves. Included criteria were patients with poorly controlled epilepsy; 18 to 65 years; At least three complex-partial or generalized ankylosing spasms per month; Non-serious or ongoing medical or psychiatric conditions; And at least two anti-epileptic drugs (AED's). Patients with vagus nerve stimulation were excluded from this study. All patients received self-administered TNS enhancement (adjunctive) treatment for at least 8 to 12 hours each day. Following a baseline period of one month, visits were made during the first three months of the month and early in the study. This initial assessment was made after visits to the epilepsy care specialist for 3 to 6 months at intervals of 3 to 6 months or after approval by the local care facility research committee.

A frequency of 120 Hertz, a current of less than 20 mA, a pulse period of 250 [mu] sec, and a pulse period of 15 to 30 [deg.] C using an electrical stimulator such as the EMS Model 7500 commercially available from TENS Products, Inc. (www.tensproducts.com, Grand Lake CO) The patient is stimulated under conditions of a duty cycle of on and 15-30 seconds off, at least 8 hours per day.

Figure 5 shows the clinical results obtained from this pilot study showing the effect of external trigeminal nerve stimulation. Five of the twelve patients experienced a reduction of more than 50% in the average 1-day seizure adjusted for 6 to 12 months of treatment. The mean reduction for 3 months was 66% and for the 12 months there was a decrease of 59% (DeGiorgio et al., Neurology 2009; 72: 936-938). Collectively, the data obtained from the table of FIG. 5 show that the trigeminal nerve stimulation using the above operating parameter values is effective in reducing seizures and is patiently tolerable for the patient under test. No serious side effects were reported. Importantly, the therapeutic effect of the device has been observed in several standard measurements, indicating the broad benefits of such treatment in various outcome measures.

Example  2

Figure 6 summarizes current, charge, current density and charge density measured in patients exposed to transdermal stimulation of the orbital nerve. Figure 6 shows the parameters for the bidirectional orbital stimulation recorded to the patient using the EMS 7500 stimulator, 120 Hz, 150-250 袖 sec, Tyco superior silver electrodes 1.25 "at 1 inch from the midline above the eyebrows. The data recorded with the Fluke oscilloscope 50 mV / div, and register = 10.1 Ω. In general, this finding shows that the pulse width is increased and the maximum allowable current is reduced.

Percutaneous electrode stimulation of the orbital nerve of the trigeminal nerve using curved 1.25-inch TENS patch electrodes results in a current density and charge density / phase within a safe range. In general, the maximum current studied in advance for TNS patients to tolerate comfortably is about 25 mA, and patients are typically stimulated with a well-set amplitude of less than 25 mA (6 to 10 mA).

1.25 inch TENS electrodes are circular electrodes with a radius of 1.59 cm. The surface area can be calculated as A = R ² = [X] X [1.59 cm ² ] = 7.92 cm ² . When using such electrodes, the typical stimulation current is in the range of 6 to 10 mA under a pulse period of 150 to 250 microseconds.

Current Density: For typical patients, stimulating currents of 6 to 10 mA are built up to a current density in the range of 0.76 to 1.3 mA / cm2. McCreery et al. Were set to have a maximum safety current density of 25 mA / cm on the stimulation electrode for DC electrical stimulation. Assuming that a high current of 25 mA is applied to the electrodes with a surface area of 7.92 cm2, the current density will be up to 3.16 mA / cm2. For a range of 0.76 mA / cm 2 to 3.16 mA / cm 2, the TNS delivers a current density that is 8 to 33 times less than the maximum safe current density. Charge density (charge density / phase): Yuen et al. Found safe limits for the charge density / phase delivered to the cerebral cortex at 40uC / cm2, and most recently, McCreery et al. (McCreery et al 1990) Which is 10 uC / cm 2. Assuming 10mA at 250usec, the charge density / phase is [.010A] x [250usec] /7.92 = 0.32uC / cm2 at the stimulation electrode. Assuming a high level of stimulation, 25 mA at 250 μs, the maximum charge density per phase is 0.79 μC / cm 2. At this level, the charge density is 12 to 120 feet at the stimulation electrode, a value less than the maximum allowed in the cerebral cortex. Since the cerebral cortex is at least 10-13 mm from the stimulating electrodes and intervening skin layers, fats, bones, cerebral membranes and CSF, the actual charge densities will be significantly lower. This is a bulk conductor and is very important in avoiding current passing through the brain tissue.

As shown in FIG. 6, the stimulus intensity response of the patient using a 7.92 cm2 surface area pulse period in the range of 150 to 250 usec was obtained by comparing the current density in the scalp with the currently recommended current density for DC stimulation, lower than 25 mA / , And the charge density in the scalp is considerably lower than the safe charge density in the cerebral cortex (0.15 to 0.18 uC / cm 2).

It will be understood by those skilled in the art that various modifications and variations of the above-described preferred embodiments can be made without departing from the spirit and scope of the invention. The stimulation of the target nerve can be achieved by applying various forms of energy, such as magnetic or ultrasound. It will therefore be appreciated that the subject matter of the present invention may be practiced otherwise than specifically described herein.

Claims (14)

As a trigeminal nerve stimulation system for the treatment of neurological diseases,
A pulse generator; And
And a subcutaneous electrode assembly electrically connected to the pulse generator,
The subcutaneous electrode assembly comprises:
A first electrode contact configured to be implanted in contact with one of the orbital nerves of the patient's forehead; And a second electrode contact configured to be implanted in contact with the other orbital nerve of the patient's forehead,
Wherein the pulse generator is configured to apply an electrical signal to the subcutaneous electrode assembly such that a current flows between the first electrode contact and the second electrode contact at specific operating parameters to treat a neurological disease,
Wherein the system is configured to infiltrate a minimal current into the brain such that the charge density at the patient &apos; s brain surface does not exceed 20 [micro] C / cm &lt; 2 &gt;. 2. The system of claim 1, further comprising a wire operatively connecting the pulse generator and the subcutaneous electrode assembly. The system of claim 1, further comprising a regulator configured to regulate a maximum charge balance output current to less than 30 to 50 mA. 3. The method of claim 1, wherein the neurological disease is selected from the group consisting of epilepsy, seizure related disorders, acute brain injury, chronic brain injury, chronic headache, migraine, diseases associated with the chronic headache and migraine, A trigeminal nerve stimulation system for the treatment of neurological disorders. The pulse generator of claim 1, wherein the pulse generator is configured to generate pulses at a frequency in the range of 20 to 300 Hertz in the cerebral cortex, a pulse period in the range of 50 to 500 microseconds, an output current density not exceeding 25 mA / cm &lt; A trigeminal nerve stimulation system for treating a neurological disorder configured to apply an electrical signal under a charge density. The method according to claim 1,
Wherein the pulse generator is configured to be implanted and wirelessly receives data or power or both data and power from outside the patient &apos; s body. The method according to claim 1,
Further comprising an external device configured to wirelessly transmit data to the pulse generator to program the operating parameters. &Lt; Desc / Clms Page number 21 &gt; The method according to claim 1,
Wherein the pulse generator is connected to the subcutaneous electrode assembly in a wireless manner. A subcutaneous electrode assembly for trigeminal nerve stimulation for the treatment of neurological disorders,
A first electrode contact configured for subcutaneous placement in one of the orbital nerves of the patient's forehead; And a second electrode contact configured for subdermal placement in the other orbital nerve of the patient's forehead, wherein when an electrical signal is applied at certain operating parameters, the first electrode contact and the second electrode contact And a current is allowed to flow between the two-electrode contacts,
Wherein the subcutaneous electrode assembly is configured to infiltrate a minimal current into the brain such that the charge density at the surface of the patient's brain does not exceed 20 [micro] C / cm &lt; 2 &gt;. 10. The method of claim 9, wherein the neurological disease is selected from the group consisting of epilepsy, seizure related disorders, acute brain injury, chronic brain injury, chronic headache, migraine, diseases associated with the chronic headache and migraine, Subcutaneous electrode assembly for trigeminal nerve stimulation for the treatment of neurological disorders. 10. The method of claim 9,
Wherein the subcutaneous electrode assembly is connected to a pulse generator through a wire. The subcutaneous electrode assembly for treating a neurological disorder according to claim 1, 10. The method of claim 9,
Wherein the subcutaneous electrode assembly is connected to the pulse generator wirelessly. The subcutaneous electrode assembly for treating a neurological disease. A kit for trigeminal nerve stimulation for the treatment of neurological diseases,
A subcutaneous electrode assembly according to claim 9; And
Instructions for implanting the subcutaneous electrode assembly in a patient for treatment of a neurological disorder. 14. The method of claim 13,
A pulse generator; And
And instructions for applying an electrical signal to the subcutaneous electrode assembly for the treatment of a neurological disorder.

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